Quality of a capsule, that is, stability of its structure, pharmacological activity of drugs as the content, and appearance thereof is closely related to the water or moisture activity. For example, it has been known that, even if a gelatin capsule was manufactured under an appropriate condition, the moisture in the capsule coating and the content drugs evaporates during preservation in a closed system, especially under heating, which possibly leads to hyper humidity condition (hyper water activity) of inside of the capsule. When a content drug comprises an active ingredient liable to change with moisture, or when moisture cannot be separated easily from an active ingredient and impurities unstable to moisture are co-exist, the content drug necessarily contacts with free water present inside of a capsule and can be un-stabilized with the elapse of time. This would result in not only the change in the appearance such as coloration but also the decrease in the activity of an active ingredient. In addition, the gelatin capsule itself may become insoluble and soft, which may be followed by the deformation or the like. In general, the adjustment of water activity, especially the reduction thereof, was carried out by placing a drying agent such as silica gel into a container for packaging capsules so as to reduce the internal moisture of a capsule. However, it is not easy to adjust the water content in the capsule coating appropriately by this method. Especially, in the case of gelatin capsules, too much decrease in the water content might cause a crack or a crack break, leading to the damage or deformation of capsules. The normal water content or moisture content of a gelatin capsule coating is between 12 and 16% and, when it becomes below 10%, in particular, below 7-8%, cracks may happen only by slight impact. Therefore, it is desirable to decrease the content of free water inside of a capsule while maintaining the water content in the gelatin coating adequately. However, the manufacture of such capsules was difficult.
There have been reported stabilized gelatin capsules, for example, in Japanese Patent Publication (KOKAI) No. 80,930/1991, Japanese Patent Publication (KOKAI) No. 145,017/1992, Japanese Patent Publication (KOKAI) No. 159,218/1992 and the like. However, they all relate to gelatin capsules which contain a stabilizer in the gelatin coating and do not mention at all about the adjustment of water activity inside of capsules. Therefore, these literatures do not solve the problems above. Japanese Patent Publication (KOKAI) No. 24,014/1978 reported gelatin capsules containing polyvinyl pyrrolidone. However, the amount of polyvinyl pyrrolidone used per capsule is only a little and the purpose of the use thereof is the adjustment of the release rate of a drug.
Under the conditions above, the present inventors have studied intensively to establish a method for adjusting the water activity inside of a capsule (i.e., internal water activity of a capsule) appropriately, and to develop a capsule having adjusted water activity.
As a result, the present invention has been established on the basis of the finding that it is useful to add a certain substance which serves as a water activity regulating agent to the capsule content in order to adjust the internal water activity of a capsule appropriately without affecting adversely the gelatin coating.